It has been demonstrated that pulmonary capillary blood pressure of strenuously exercising horses increases dramatically. Therefore, alveolar-capillary blood-gas barrier, which has to be extremely thin to provide for passive diffusion of O.sub.2, is exposed to high transmural pressures resulting in its stress failure and the ensuing exercise induced pulmonary hemorrhage (EIPH). The rapid rate of rise in pulmonary capillary blood pressure of Thoroughbreds upon rapid acceleration is probably another factor which contributes to onset of EIPH very early in the course of a race. Logically, in the context of preventing EIPH, the pulmonary blood-gas barrier therefore needs to be strengthened and or the pulmonary vascular pressures of racing Thoroughbreds be lower. Whereas the former may require genetic manipulation (thickness of pulmonary blood-gas barrier must not increase however, because of impediment to gas exchange), the latter may be accomplished with selective pulmonary vasodilator agents. It is known that pre-exercise administration of fursemide attenuates significantly the exercise induced rise in pulmonary vascular pressures of horses.
At sea level, in resting animals and man, pulmonary vascular pressures are about 1/4 to 1/3 of those in the systemic circulation because pulmonary vascular resistance is kept at a very low level; in standing horses pulmonary vascular resistance was only 1/10th of the systemic vascular resistance. It has been suggested (Griffith et al. 1987; Ignarro 1989) that pulmonary vascular bed of normoxic resting animals is kept in a dilated state by the tonic release of nitric oxide (NO; also known as endothelium derived relaxing factor of EDRF). Experiments in several species (cat, rabbit, guinea pig and lamb) have demonstrated that inhibition of the NO synthesis increase basal tone in pulmonary vascular bed. It has been demonstrated that NO inhalation reversed pulmonary vasoconstriction induced by alveolar hypoxia in adult sheep. The pulmonary vasodilator effect of exogenously administered acetylcholine is believed to be mediated via release of NO (Ignarro 1989). Increased blood velocity/shear rate is also known to promote release of NO from the vascular endothelium (Griffith et al. 1987; Cooke et al. 1990; Griffith and Edwards 1990). The vascular smooth muscle relaxant action of nitrovasodilators such as amyl nitrate, glyceryl trinitrate (nitroglycerin) and nitroprusside, is via activation of soluble guanylate cyclase, which elevates the intracellular cyclic GMP level (Ignarro 1989).
A gaseous nitric oxide-donor treatment of vasoconstriction is known. U.S. Pat. No. 5,480,869 discloses anti-inflammatory peptide analogs and their use as a treatment for inhibiting vascular leakage in injured tissues, including damaged lungs tissue. Several peptides in this patent include arginine, but the patent does not suggest using the amino acid L-arginine independently. The patent discloses intravenous, intradermal and subcutaneous administration, but makes no suggestion of any gaseous applications of the peptide analogs.
U.S. Pat. No. 5,485,827 discloses methods and devices for treating pulmonary vasoconstriction and asthma. The patent indicates that a mammal at risk of developing pulmonary vasoconstriction may be treated with a therapeutically effective amount of a nitric oxide-releasing compound. Also disclosed is a portable inhaler that could be used to administer inhalation therapy for pulmonary vasoconstriction.
"Effects Of Glyceryl Trinitrate (Nitroglycerine) On Pulmonary Vascular Pressures In Standing Thoroughbred Horses", Manohar, M, Equine Vet. J., (July, 1995) 27(4):275-80; discloses using nitroglycerine to lower the blood pressure of thoroughbred horses and allegedly prevent exercise-induced pulmonary hemorrhaging. The article concentrates on the use of nitroglycerine and not on the use of L-arginine.
There is a need in the art for alternative treatments for EIPH. The present invention overcomes the deficiencies of the prior art by providing a composition and an inhaler apparatus for the treatment of EIPH.